Extended release, abuse deterrent dosage forms

ABSTRACT

Extended release, abuse deterrent dosage forms comprising crush-resistant controlled-release particles that provide abuse deterrent properties to the dosage forms. The crush-resistant controlled-release particles, which comprise plastic/elastic polymers and at least one active pharmaceutical ingredient (API) or a pharmaceutically acceptable salt thereof, are prepared by a hot melt extrusion process.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/464,865, filed Mar. 21, 2017, which claims the priority of U.S.Provisional Application Ser. No. 62/315,952, filed Mar. 31, 2016, thedisclosure of each is hereby incorporated by reference in its entirety.

FIELD

The present disclosure generally relates to extended release, abusedeterrent dosage forms comprising a plurality of crush-resistantcontrolled-release particles comprising an active ingredient, whereinthe particles are prepared by a hot melt extrusion process.

BACKGROUND

Abuse of prescription drugs (particularly opioids) has become a serioussocietal problem. Such abuse places an enormous economic burden onsociety due to increased health care, work place, and criminal justicecosts. Several routes of administration are commonly attempted byabusers. For example, the oral solid dosage form may be crushed orpulverized into a powder and administered by an intranasal route (i.e.,snorted), or dissolved in a suitable solvent (e.g., water) andadministered by a parenteral route (i.e., injected intravenously),swallowed after chewing in the mouth, or swallowed after physicalmanipulation.

Attempts have been made to diminish the abuse of opioid solid dosageforms. One approach has been to include in the dosage form an opioidantagonist that is not orally active but will substantially block theanalgesic effects of the opioid if one attempts to dissolve the opioidand administer it parenterally. Another approach has been to includegel-forming high molecular weight polymers that confer plasticity to thedosage form rendering them difficult to crush and pulverize into powder.A commercially available extended release, abuse deterrent tablet ofoxycodone HCl utilizes a physical barrier to deter both physicalmanipulations (e.g., reduction of the particle size using commonhousehold tools and chemical extraction of oxycodone HCl in aninjectable solvent). However, these abuse deterrent tablets are stillbeing abused by swallowing after chewing, swallowing after physicalmanipulation, and IV injection after the extraction of oxycodone HCl ina small volume of water (<10 mL) from both intact and cut tablets.

Thus, there is a need for oral dosage forms that provide extendedrelease of the active ingredient yet are resistant to abuse by oral,intranasal, and IV injection via chewing, grinding, and chemicalextraction.

SUMMARY

One aspect of the present disclosure encompasses an extended release,abuse deterrent dosage form comprising a plurality of particles and atleast one pharmaceutically acceptable excipient. The plurality ofparticles comprises at least two plastic/elastic polymers and at leastone active pharmaceutical ingredient (API) or a pharmaceuticallyacceptable salt thereof. The particles included in the dosage formsprovide abuse deterrent features and provide extended release of theAPI.

Other aspects and iterations of the disclosure are described in moredetail below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 presents the in vitro dissolution profiles of crush-resistantcontrolled-release particulate systems (CRCRPS) before and aftergrinding in a coffee grinder.

DETAILED DESCRIPTION

The present disclosure provides extended release dosage forms that haveabuse deterrent properties. The dosage forms comprise crush-resistantcontrolled-release particles that are produced by hot melt extrusion.The crush-resistant controlled-release particles deter oral abuse bychewing, intranasal abuse by milling and grinding, and IV injectionabuse after extraction of an active pharmaceutical ingredient. Alsoprovided herein are processes for preparing the crush-resistantcontrolled-release particles and processes for preparing dosage formscomprising the crush-resistant controlled-release particles.

(I) Particles

One aspect of the present disclosure provides crush-resistantcontrolled-release particles. The particles comprise at least oneplastic/elastic polymer and at least one pharmaceutical ingredient (API)or a pharmaceutically acceptable salt thereof. Typically, the particlesfurther comprise at least one plasticizer, at least one lubricant, orcombinations thereof. In some embodiments, the particles may furthercomprise at least one wetting agent. The particles are prepared by a hotmelt extrusion process as detailed below in section (III)(a). Thecomposition of the particles imparts sufficient mechanical integrity(e.g., hardness, resilience, etc.) such the particles are resistant tocrushing, grinding, milling, or pulverizing to form a fine powder.Additionally, the particles have a slow rate of dissolution such thatrelease of the API is extended, i.e., it proceeds over a span of hours.Thus, the particles disclosed herein are crush-resistantcontrolled-release particles (and are also known as a crush-resistantcontrolled-release particle system or CRCRPS).

The components of the crush-resistant controlled-release particles aredetailed below.

(a) Plastic/Elastic Polymers

The crush-resistant controlled-release particles comprise at least oneplastic/elastic polymer. A plastic/elastic polymer generally refers to amaterial that becomes pliable or moldable above a certain temperatureand solidifies upon cooling.

The identity of the plastic/elastic polymer(s) included in thecrush-resistant controlled-release particles can and will vary dependingupon the desired properties (e.g., resilience to physical manipulation)of the particles. The plastic/elastic polymer may be synthetic,semi-synthetic, or natural; the plastic/elastic polymer may be solublein water or insoluble in water. The weight average molecular weightdistribution of the plastic/elastic polymer may range from about 20,000to more than 7,000,000.

In some embodiments, the plastic/elastic polymer may be a polyvinylester such as, e.g., polyvinyl acetate, polyvinyl propionate, polyvinylbutyrate, and the like. An exemplary polyvinyl ester is polyvinylacetate (PVAc), copolymers thereof, and derivatives thereof (e.g.,polyvinyl alcohol). In embodiments in which the plastic/elastic polymeris polyvinyl acetate, the weight average molecular weight distributionof polyvinyl acetate can range from about 100,000 to about 500,000.

In other embodiments, the plastic/elastic polymer may be apoly-N-vinylamide, such as polyvinylpyrrolidone or polyvinylcaprolactam. An exemplary poly-N-vinylamide is polyvinylpyrrolidone(also called PVP or povidone) or copolymers thereof. The averagemolecular weight of polyvinylpyrrolidone can range from several thousandto about 1.5 million.

In further embodiments the plastic/elastic polymer may be a blend ofpolyvinyl acetate and polyvinylpyrrolidone (also calledpoly(vinylpyrrolidone-co-vinyl acetate) or polyvinylacetate-polyvinylpyrrolidone). The weight ratio of polyvinyl acetate topolyvinylpyrrolidone may be about 1:9, about 2:8, about 3:7, about 4:6,about 5:5, about 6:4, about 7:3, about 8:2, or about 9:1. Blends ofpolyvinyl acetate-polyvinylpyrrolidone are available under the tradename KOLLIDON® VA64 (in which the ratio of polyvinylpyrrolidone topolyvinyl acetate is 6:4) or KOLLIDON® SR (in which the ratio ofpolyvinyl acetate to polyvinylpyrrolidone to about 4:1, i.e., containsabout 80% of polyvinyl acetate having an average weight molecular weightdistribution of about 450,000 and about 19% of polyvinylpyrrolidonehaving an average weight molecular weight distribution of about 50,000).The blend may further comprise sodium lauryl sulfate and/or silicondioxide as stabilizer(s) or flowability agent(s).

In additional embodiments, the plastic/elastic polymer may be apolyalkylene oxide, such as polyethylene oxide, polypropylene oxide,copolymers, or derivatives thereof. An exemplary polyalkylene oxide ispolyethylene oxide. The average weight molecular weight distribution ofthe polyethylene oxide can range from about 100,000 to 7 million ormore.

In still other embodiments, the plastic/elastic polymer may be acellulose derivative such as cellulose esters (e.g., cellulose acetate)or cellulose ethers. Non-limiting examples of suitable cellulose ethersinclude hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethylcellulose, carboxymethyl cellulose, mixtures, and derivatives thereof.The average molecular weight distribution of cellulose ethers can rangefrom about 20,000 to about 1.5 million.

In still other embodiments, the plastic/elastic polymer may be anacrylic acid polymer (i.e., polyacrylic acid), a methacrylic acidpolymer, an acrylate polymer (e.g., methylacrylate polymer,ethylacrylate polymer), a methacrylate polymer (e.g., methyl methacylatepolymer, etc.), a copolymer thereof, or a derivative thereof. Suitablepolyacrylic acids include carbomers, which are homopolymers of acrylicacid cross linked with polyalcohol allyl ethers (e.g., allyl etherpentaerythritol, allyl ether of sucrose, or allyl ether of propylene),and polycarbophil, which is a homopolymer of acrylic acid cross linkedwith divinyl glycol. Examples of suitable copolymers include a copolymerof ethyl acrylate and methyl methacrylate, copolymer of ethyl acrylate,methyl methacrylate, and methacrylic acid ester with quaternary ammoniumgroups, copolymer of methacrylic acid and ethylacrylate, and the like.

Other suitable plastic/elastic polymers include polycarboxylic acids;polyamines, natural gums (e.g., polysaccharides derived from botanicalsources or seaweeds, or produced via bacterial fermentation), starches,pectins, alginates, polypeptides (such as, e.g., gelatin, albumin,polylysine, soy protein, and so forth); and combinations thereof.

The amount of the plastic/elastic polymer(s) present in thecrush-resistant controlled-release particles can and will vary dependingupon the identity of the polymer and the desired properties (e.g.,strength, mechanical integrity, rate of dissolution, and the like) ofthe particles. In general, the amount of plastic/elastic polymer presentin the particles may range from about 30% to about 90% by weight of theparticles. In various embodiments, the amount of plastic/elastic polymermay be about range from about 30% to about 40%, from about 40% to about50%, from about 50% to about 60%, from about 60% to about 70%, fromabout 70% to about 80% by weight of the particles.

(b) Plasticizers

The crush-resistant controlled-release particles also comprise at leastone plasticizer. In general, plasticizers increase the fluidity orflexibility of polymers, making them easier to handle or process. Theplasticizer(s) included in the particles may be hydrophilic,hydrophobic, or a combination thereof. Examples of suitable plasticizersinclude but are not limited to glycerin (glycerol), polyethylene glycols(e.g., PEG 300, PEG 400, PEG 600, etc.), polyethylene glycol monomethylether, propylene glycol, sorbitol sorbitan solution, triethyl cellulose,dicarboxylic acid esters (e.g., sebacic acid, azelaic acid), acetyltributyl citrate, acetyl triethyl citrate, castor oil, vegetable oils,diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate,triacetin, tributyrin, tributyl citrate, triethyl citrate, polaxamers(i.e., triblock copolymers of polyethylene oxide and polypropyleneoxide), or combinations thereof. In one embodiment, the plasticizer maybe diethyl phthalate. In another embodiment, the plasticizer may be acombination of diethyl phthalate and polyethylene glycol.

The amount of plasticizer present in the particles can and will varydepending upon the identity of the plastic/elastic polymer(s) and thedesired release properties of the particles. In general, the amount ofplasticizer present in the particles may range from about 2% to about75% by weight of the total weight of the plastic/elastic polymer. Invarious embodiments, the amount of plasticizer may range from about 2%to about 10%, from about 10% to about 30%, from about 30% to about 50%,or from about 50% to about 75% by weight of the total weight of theplastic/elastic polymer.

(c) Lubricants

The crush-resistant controlled-release particles also comprise at leastone lubricant. Non-limiting examples of suitable lubricants includemagnesium stearate, calcium stearate, zinc stearate, colloidal silicondioxide, hydrogenated vegetable oils, sterotex, polyoxyethylenemonostearate, polyethylene glycol, sodium stearyl fumarate, sodiumbenzoate, sodium lauryl sulfate, magnesium lauryl sulfate, light mineraloil, or combinations thereof. In one embodiment, the lubricant may bemagnesium stearate.

The amount of lubricant present in the particles can and will varydepending upon the identity and amount of the other components. Ingeneral, the amount of lubricant may range from about 0.1% to about 3.0%by weight of the particles. In various embodiments, the amount oflubricant may range from about 0.2% to about 2.0%, from about 0.5% toabout 1.5%, or from about 0.8% to about 1.2% by weight of the particles.In specific embodiments, the amount of the lubricant may be about 1% byweight of the particles.

(d) Wetting Agents

The crush-resistant controlled-release particles may further comprise atleast one wetting agent. Wetting agents increase the spreading andpenetrating properties of a liquid by lowering its surface tension.Suitable wetting agents include surfactants and/or emulsifiers.Non-limiting example of suitable surfactants include nonionicsurfactants (e.g., polyoxyethylene glycol alkyl ethers, polyoxyethyleneglycol sorbitan alkyl esters, polyethylene glycol esters, blockco-polymers of polyethylene glycol and polypropylene glycol,polyoxyethylene fatty acid amides, ethoxylated aliphatic alcohols,alkylphenols, and the like), anionic surfactants (e.g., alkyl sulfatessuch as sodium lauryl sulfate or ammonium lauryl sulfate, alkylsulfonates, alkyl benzene sulfonates, alpha sulfonyl fatty acids, alkylphosphates, dioctyl sulfosuccinate, isethionates, alkyl ether sulfates,methyl sarcosines and the like), cationic surfactants (e.g.,alkyltrimethylammonium bromide; cetyltrimethylammonium bromide,benzalkonium chloride; benzethonium chloride, and so forth), andzwitterionic surfactants (e.g., CHAPS, lecithin, cocoaminopropylbetaine, and so forth). Suitable emulsifiers include sorbitan fatty acidesters such as sorbitan monooleate or sorbitan monostearate, glycerylfatty acid esters such as glyceryl monooleate or glyceryl monosteareate,polyethylene glycols, glycerol, block co-polymers of polyethylene glycoland polypropylene glycol, polaxamers, polysorbates, and the like). Theamount of wetting agent present in the particles can and will varydepending upon the identity of the wetting agent and the othercomponents of the particles.

The amount of wetting present in the particles can and will varydepending, for example, on the identity and amount of the othercomponents present in the particles. In general, the amount of wettingagent present in the particles may range from about 2% to about 75% byweight of the total weight of the particles. In various embodiments, theamount of wetting agent may range from about 2% to about 10%, from about10% to about 30%, from about 30% to about 50%, or from about 50% toabout 75% by weight of the total weight of the particles.

(e) APIs

The crush-resistant controlled-release particles also comprise at leastone API or a pharmaceutically acceptable salt thereof. Suitable APIsinclude, without limit, opioid analgesic agents (e.g., adulmine,alfentanil, allocryptopine, allylprodine, alphaprodine, anileridine,aporphine, benzylmorphine, berberine, bicuculine, bicucine, bezitramide,buprenorphine, bulbocaprine, butorphanol, clonitazene, codeine,desomorphine, dextromoramide, dezocine, diampromide, diamorphone,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, nalbuphine, nalmefene, normorphine,norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine,phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, propheptazine, promedol, properidine, propoxyphene,sufentanil, tapentadol, tilidine, and tramadol); opioid antagonists(e.g., naloxone, naltrexone, alvimopan, cyprodime, diprenorphine,gemazocine, 5′-guanidinonaltrindole, levallorphan, methylnaltrexone,naldemedine, nalmexone, nalorphine, naloxazone, naloxol, naloxonazine,6β-naltrexol-d4, naltriben, naltrindole, norbinaltorphimine, oxilorphan,quadazocine, and samidorphan); non-opioid analgesic agents (e.g.,acetylsalicylic acid, acetaminophen, paracetamol, ibuprofen, ketoprofen,indomethacin, diflunisol, naproxen, ketorolac, dichlophenac, tolmetin,sulindac, phenacetin, piroxicam, and mefamanic acid); anti-inflammatoryagents (e.g., glucocorticoids such as alclometasone, fluocinonide,methylprednisolone, triamcinolone and dexamethasone; non-steroidalanti-inflammatory agents such as celecoxib, deracoxib, ketoprofen,lumiracoxib, meloxicam, parecoxib, rofecoxib, and valdecoxib);antitussive agents (e.g., dextromethorphan, codeine, hydrocodone,caramiphen, carbetapentane, and dextromethorphan); antipyretic agents(e.g., acetylsalicylic acid and acetaminophen); antibiotic agents (e.g.,aminoglycosides such as, amikacin, gentamicin, kanamycin, neomycin,netilmicin, streptomycin, and tobramycin; carbecephem such asloracarbef; carbapenems such as certapenem, imipenem, and meropenem;cephalosporins such as cefadroxil cefazolin, cephalexin, cefaclor,cefamandole, cephalexin, cefoxitin, cefprozil, cefuroxime, cefixime,cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime,ceftazidime, ceftibuten, ceftizoxime, and ceftriaxone; macrolides suchas azithromycin, clarithromycin, dirithromycin, erythromycin, andtroleandomycin; monobactam; penicillins such as amoxicillin, ampicillin,carbenicillin, cloxacillin, dicloxacillin, nafcillin, oxacillin,penicillin G, penicillin V, piperacillin, and ticarcillin; polypeptidessuch as bacitracin, colistin, and polymyxin B; quinolones such asciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin,moxifloxacin, norfloxacin, ofloxacin, and trovafloxacin; sulfonamidessuch as mafenide, sulfacetamide, sulfamethizole, sulfasalazine,sulfisoxazole, and trimethoprim-sulfamethoxazole; tetracyclines such asdemeclocycline, doxycycline, minocycline, and oxytetracycline);antimicrobial agents (e.g., ketoconazole, amoxicillin, cephalexin,miconazole, econazole, acyclovir, and nelfinavir); antiviral agents(e.g., acyclovir, gangciclovir, oseltamivir, and relenza); steroids(e.g., estradiol, testosterone, cortisol, aldosterone, prednisone, andcortisone); amphetamine stimulant agents (e.g., amphetamine andamphetamine-like drugs); non-amphetamine stimulant agents (e.g.,methylphenidate, nicotine, and caffeine); laxative agents (e.g.,bisacodyl, casanthranol, senna, and castor oil); anti-nausea agents(e.g., dolasetron, granisetron, ondansetron, tropisetron, meclizine, andcyclizine); anorexic agents (e.g., fenfluramine, dexfenfluramine,mazindol, phentermine, and aminorex); antihistaminic agents (e.g.,phencarol, cetirizine, cinnarizine, ethamidindole, azatadine,brompheniramine, hydroxyzine, and chlorpheniramine); antiasthmaticagents (e.g., zileuton, montelukast, omalizumab, fluticasone, andzafirlukast); antidiuretic agents (e.g., desmopressin, vasopressin, andlypressin); antimigraine agents (e.g., naratriptan, frovatriptan,eletriptan, dihydroergotamine, zolmitriptan, almotriptan, andsumatriptan); antispasmodic agents (e.g., dicyclomine, hyoscyamine, andpeppermint oil); antidiabetic agents (e.g., methformin, acarbose,miglitol, pioglitazone, rosiglitazone, nateglinide, repaglinide,mitiglinide, saxagliptin, sitagliptine, vildagliptin, acetohexamide,chlorpropamide, gliclazide, glimepiride, glipizide, glyburide,tolazamide, and tolbutamide); respiratory agents (e.g., albuterol,ephedrine, metaproterenol, and terbutaline); sympathomimetic agents(e.g., pseudoephedrine, phenylephrine, phenylpropanolamine, epinephrine,norepinephrine, dopamine, and ephedrine); H2 blocking agents (e.g.,cimetidine, famotidine, nizatidine, and ranitidine); antihyperlipidemicagents (e.g., clofibrate, cholestyramine, colestipol, fluvastatin,atorvastatin, genfibrozil, lovastatin, niacin, pravastatin, fenofibrate,colesevelam, and simvastatin); antihypercholesterol agents (e.g.,lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin,cholestyramine, colestipol, colesevelam, nicotinic acid, gemfibrozil,and ezetimibe); cardiotonic agents (e.g., digitalis, ubidecarenone, anddopamine); vasodilating agents (e.g., nitroglycerin, captopril,dihydralazine, diltiazem, and isosorbide dinitrate); vasoconstrictingagents (e.g., dihydroergotoxine and dihydroergotamine); anticoagulants(e.g., warfarin, heparin, and Factor Xa inhibitors); sedative agents(e.g., amobarbital, pentobarbital, secobarbital, clomethiazole,diphenhydramine hydrochloride, and alprazolam); hypnotic agents (e.g.,zaleplon, zolpidem, eszopiclone, zopiclone, chloral hydrate, andclomethiazole); anticonvulsant agents (e.g., lamitrogene,oxycarbamezine, phenytoin, mephenytoin, ethosuximide, methsuccimide,carbamazepine, valproic acid, gabapentin, topiramate, felbamate, andphenobarbital); muscle relaxing agents (e.g., baclofen, carisoprodol,chlorzoxazone, cyclobenzaprine, dantrolene sodium, metaxalone,orphenadrine, pancuronium bromide, and tizanidine); antipsychotic agents(e.g., phenothiazine, chlorpromazine, fluphenazine, perphenazine,prochlorperazine, thioridazine, trifluoperazine, haloperidol,droperidol, pimozide, clozapine, olanzapine, risperidone, quetiapine,ziprasidone, melperone, and paliperidone); antianxiolitic agents (e.g.,lorazepam, alprazolam, clonazepam, diazepam, buspirone, meprobamate, andflunitrazepam); antihyperactive agents (e.g., methylphenidate,amphetamine, and dextroamphetamine); antihypertensive agents (e.g.,alpha-methyldopa, chlortalidone, reserpine, syrosingopine, rescinnamine,prazosin, phentolamine, felodipine, propanolol, pindolol, labetalol,clonidine, captopril, enalapril, and lisonopril); anti-neoplasia agents(e.g., taxol, actinomycin, bleomycin A2, mitomycin C, daunorubicin,doxorubicin, epirubicin, idarubicin, and mitoxantrone); soporific agents(e.g., zolpidem tartrate, eszopiclone, ramelteon, and zaleplon);tranquilizer agents (e.g., alprazolam, clonazepam, diazepam,flunitrazepam, lorazepam, triazolam, chlorpromazine, fluphenazine,haloperidol, loxapine succinate, perphenazine, prochlorperazine,thiothixene, and trifluoperazine); decongestant agents (e.g., ephedrine,phenylephrine, naphazoline, and tetrahydrozoline); beta blockers (e.g.,levobunolol, pindolol, timolol maleate, bisoprolol, carvedilol, andbutoxamine); alpha blockers (e.g., doxazosin, prazosin,phenoxybenzamine, phentolamine, tamsulosin, alfuzosin, and terazosin);non-steroidal hormones (e.g., corticotropin, vasopressin, oxytocin,insulin, oxendolone, thyroid hormone, and adrenal hormone); erectiledisfunction improvement agents; herbal agents (e.g., glycyrrhiza, aloe,garlic, nigella sativa, rauwolfia, St John's wort, and valerian);enzymes (e.g., lipase, protease, amylase, lactase, lysozyme, andurokinase); humoral agents (e.g., prostaglandins, natural and synthetic,for example, PGE1, PGE2alpha, PGF2alpha, and the PGE1 analogmisoprostol); psychic energizers (e.g., 3-(2-aminopropy)indole and3-(2-aminobutyl)indole); nutritional agents; essential fatty acids;non-essential fatty acids; vitamins; minerals; and combinations thereof.

Any of the above-mentioned APIs may be incorporated in the particlesdescribed herein in any suitable form, such as, for example, as apharmaceutically acceptable salt, uncharged or charged molecule,molecular complex, solvate or hydrate, prodrug, and, if relevant,isomer, enantiomer, racemic mixture, and/or mixtures thereof.Furthermore, the API may be in any of its crystalline, semi-crystalline,amorphous, or polymorphous forms.

In one embodiment, the API present in the crush-resistantcontrolled-release particles may have a potential for abuse. Forexample, the API may be an opioid analgesic agent, a stimulant agent, asedative agent, a hypnotic agent, an antianxiolitic agent, or a musclerelaxing agent.

In another embodiment, the API present in the crush-resistantcontrolled-release particles may be a combination of an opioid analgesicand a non-opioid analgesic. Suitable opioid and non-opioid analgesicsare listed above.

In exemplary embodiments, the API in the crush-resistantcontrolled-release particles may be an opioid analgesic. Exemplaryopioid analgesics include oxycodone, oxymorphone, hydrocodone,hydromorphone, codeine, morphine, or pharmaceutically acceptable saltthereof. In an exemplary embodiment, the API may be oxycodonehydrochloride. In another exemplary embodiment, the API may beoxymorphone hydrochloride.

The amount of API in the crush-resistant controlled-release particlescan and will vary depending upon the active agent and the desired doseof API in the final dosage form. In general, the amount of API in theparticles may range from about 2% to about 70% by weight of theparticles. In various embodiments, the amount of API may range fromabout 2% to about 5%, from about 5% to about 10%, from about 10% toabout 20%, from about 20% to about 30%, from about 30% to about 40%,from about 40% to about 50%, from about 50% to about 60%, or from about60% to about 70% by weight of the particles.

(f) Exemplary Particles

In specific embodiments, the crush-resistant controlled-releaseparticles may comprise a blend of polyvinylacetate-polyvinylpyrrolidone, one or more plasticizers, a lubricant,optionally at least one wetting agent, and optionally a polyethyleneoxide. The plasticizer may comprise diethyl phthalate and polyethyleneglycol. The lubricant may be magnesium stearate. The optional wettingagent may be an alkyl sulfate or a sorbitan fatty acid ester. Thepolyethylene oxide may have an average molecule weight of about 100,000.

(g) Size of Particles

The size of the particles disclosed herein can and will vary. Ingeneral, the particles are too large to be inhaled or insufflated.Typically, the size distribution of the particles may range from about50 micrometers (μm) to about 1500 μm. In some embodiments, the particlesize distribution may range from about 100 lam to about 1000 μm. Theparticle distribution also can be described using D values. For examplethe D10 diameter is the diameter at which 10% of a sample's mass iscomprised of smaller particles, and the D50 is the diameter at which 50%of a sample's mass is comprised of smaller particles. Thus, the D50 isthe mass median diameter. In certain embodiments, the D50 of theparticles may be about 150 μm, about 200 μm, about 300 μm, about 400 μm,about 450 μm, about 500 μm, about 550 μm, about 600 μm, about 650 μm,about 700 μm, about 750 μm, about 800 μm, about 850 μm, about 900 μm,about 950 μm, or about 1000 μm, and the D10 of the particles may beabout 75 μm, about 100 μm, about 200 μm, about 300 μm, about 400 μm,about 500 μm, about 600 μm, about 700 μm, or about 800 μm.

(h) Physical Properties of the Particles

The particles disclosed herein are formed by a melt extrusion process(see section (III)(a) below). The combination of plastic/elasticpolymers and other components in the particles imparts sufficientmechanical integrity (i.e., strength, hardness, etc.) such that theparticles are resistant to crushing, grinding, milling, or pulverizingto form a fine powder or particles that are small enough to be snortedor insufflated. In general, particles suitable for insufflation are lessthan about 20 μm, less than about 10 μm, or less than about 5 μm. Theparticles formed by melt extrusion disclosed herein may be milled orground in a coffee grinder, a coffee mill, a blender, a spice grinder, apill crusher, as tablet grinder, a ball mill, a co-mill, a high-shearmill, or another apparatus to reduce particle size. After milling orgrinding for a period of time ranging from about 15 seconds up to about10 minutes, the D50 of the particles may be reduced by less than aboutthan 5%, less than about 10%, less than about 15%, less than about 20%,less than about 25%, less than about 30%, less than about 35%, less thanabout 40%, or less than about 50%.

In some embodiments, the size of the particles formed by melt extrusiondisclosed herein may increase as the grinding or milling time increases.For example, the average particle size of the plurality of particlesincreases after being ground or milled for more than about 3 minutes.While not being bound to a particular theory, it is hypothesized thatthe heat generated during the grinding or milling process is sufficientto melt the plastic/elastic polymers in the particles causing theparticles or fragments thereof to agglomerate into larger sizedparticles.

In additional embodiments, the mechanical integrity of the particles maybe accessed by measuring the breaking point or the breaking strength ofthe particles. The breaking point refers to the amount of applied forceneeded to compromise the integrity of the particle. The force necessaryto determine the breaking point may be generated using a TextureAnalyzer model TA.XT. Plus (Texture Technologies Corp.), an InstronUniversal Tester (Instron Engineering Corp.), or other suitableinstrument. The particles may exhibit a breaking point of greater thanabout 300 Newtons (N), greater that about 500 N, or greater than about1000 N. Alternatively the particles may not exhibit a breaking point.Rather the particles may flatten or deform (without breaking) uponapplication of increasing force.

(i) In Vitro Release Profile of the Particles

The composition of the particles controls the rate of dissolution of theparticles. In particular, the rate of dissolution of the particlesdisclosed herein is slow (i.e., is controlled by time). As aconsequence, the rate of API release from the particles is slow orextended. Thus, the API is released from the particles over an extendedperiod of time during in vitro dissolution testing. For example, thetotal amount of API may be released over a period of about 6 hours, overa period of about 12 hours, over a period of about 18 hours, or over aperiod of about 24 hours.

The in vitro dissolution of the API from the particles disclosed hereinmay be measured using an approved USP procedure. For example,dissolution may be measured using an USP approved Type 2 paddleapparatus, at a paddle speed of 50 rpm or 100 rpm, and a constanttemperature of 37±0.5° C. The dissolution test may be performed in thepresence of 500 mL, 900 mL, or 1,000 mL of a suitable dissolution medium(e.g., having a pH from about 1.0 to about 7.0). Non-limiting examplesof suitable dissolution media include water, simulated gastric fluid(SGF), phosphate buffer (pH 6.8), acetate buffer (pH 4.5), and 0.1N HCl.

In various embodiments, the in vitro release of the API from theparticles is such that no more than about 50%, 60%, 70%, 80%, 90% or 95%of the API is released within about 6 hours, 8 hours, 12 hours, 18hours, or 24 hours. In one embodiment, no more than about 80% of the APIis released within about 6 hours. In another embodiment, no more thanabout 80% of the API is released within about 8 hours. In a furtherembodiment, no more than about 80% of the API is released within about12 hours. In yet another embodiment, no more than about 80% of the APIis released within about 18 hours. In an alternate embodiment, no morethan about 80% of the API is released within about 24 hours.

(II) Dosage Forms

Another aspect of the present disclosure encompasses dosage formscomprising the crush-resistant controlled-release particles describedabove in section (I). In general, the dosage form is a solid dosage formthat is formulated for oral administration. The solid dosage form may bea tablet or a capsule. Suitable tablets include orallydisintegrating/dissolving tablets, fast disintegrating/dissolvingtablets, and conventional tablets.

(a) Tablets

In some embodiments, the dosage form is a tablet. The term “tablet”includes tablets, caplets, pills, compacts, and pellets of any shape orsize that optionally may be scored. In certain iterations, the tabletmay be an orally disintegrating/dissolving tablet (also called anorodispersible tablet or ODT), which disintegrates quickly in the mouthin the presence of saliva to be swallowed without the need for water. Inother iterations, the tablet may be a fast disintegrating/dissolvingtablet (FTD) or quickly disintegrating/dissolving tablet. The fastdisintegrating/dissolving tablet can be swallowed intact and rapidlydisintegrate in the stomach. Alternatively, the fastdisintegrating/dissolving tablet can be readily dispersed in water toform a dispersion that is easy to swallow. In general, orallydisintegrating/dissolving tablets and fast disintegrating/dissolvingtablets disintegrate or disperse within less than about 3 minutes, lessthan about 2 minutes, less than about 1 minute, or less than about 30seconds. However, even though the tablet may disintegrate quickly andrelease the particles, the properties of the particles do not change,i.e., they remain crush resistant and provide controlled release of theAPI. In still other iterations, the tablet may be a conventional tablet,i.e., a tablet that takes longer than about 3 minutes to disintegrate ordissolve.

The tablet dosage form comprises a plurality of the crush-resistantcontrolled-release particles disclosed herein and one or morepharmaceutically acceptable excipients. The pharmaceutically acceptableexcipient(s) may be chosen from binders, fillers, super-disintegrants,lubricants, ion exchange resin powders, or combinations thereof. In someembodiments, the tablet may further comprise at least one aversiveagent.

Binders.

In some embodiments, the tablet may comprise one or more binders.Non-limiting examples of suitable binders include starches (e.g., cornstarch, potato starch, wheat starch, rice starch, and the like),pregelatinized starch, hydrolyzed starch, cellulose, microcrystallinecellulose, cellulose derivatives (e.g., methylcellulose, ethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose, sodiumcarboxymethylcellulose, and the like), saccharides (e.g., sucrose,lactose, and so forth), sugar alcohols (e.g., maltitol, sorbitol,xylitol, polyethylene glycol, and the like), alginates (e.g., alginicacid, alginate, sodium alginate, and so forth), gums (e.g., gum arabic,guar gum, gellan gum, xanthan gum, and the like), pectins, gelatin,C12-C18 fatty acid alcohols, polyvinylpyrrolidinone (also calledcopovidone), polyethylene oxide, polyethylene glycol, polyvinylalcohols, waxes (e.g., candelilla wax, carnauba wax, beeswax, and soforth), or combinations of any of the forgoing. In embodiments in whichbinder is present in the tablet, the amount of binder may range fromabout 0.1% to about 50% by weight of the total weight of the tablet. Invarious embodiments, the amount of binder may range from about 0.1% toabout 10%, from about 10% to about 20%, from about 20% to about 30%,from about 30% to about 40%, or from about 40% to about 50% by weight ofthe total weight of the tablet.

Fillers.

In other embodiments, the tablet may comprise one or more fillers (alsocalled diluents). Suitable fillers include without limit cellulose,microcrystalline cellulose, cellulose ethers (e.g., ethyl cellulose,methyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, etc.), cellulose esters(i.e., cellulose acetate, cellulose butyrate, and mixtures thereof),starches (e.g., corn starch, rice starch, potato starch, tapioca starch,and the like), modified starches, pregelatinized starches, phosphatedstarches, starch-lactose, starch-calcium carbonate, sodium starchglycolate, glucose, fructose, sucrose, lactose, xylose, lactitol,mannitol, malitol, sorbitol, xylitol, maltodextrin, trehalose, calciumcarbonate, calcium sulfate, calcium phosphate, calcium silicate,magnesium carbonate, magnesium oxide, talc, or combinations thereof. Incertain embodiments, the filler may also function as a taste-maskingagent. Taste-masking agents include cellulose ethers, polyethyleneglycols, polyvinyl alcohol, polyvinyl alcohol and polyethylene glycolcopolymers, monoglycerides or triglycerides, acrylic polymers, mixturesof acrylic polymers with cellulose ethers, cellulose acetate phthalate,and combinations thereof. In embodiments in which filler is present inthe tablet, the amount of filler may range from about 0.1% to about 50%by weight of the total weight of the tablet. In certain embodiments, theamount of filler may range from about 0.1% to about 10%, from about 10%to about 20%, from about 20% to about 30%, from about 30% to about 40%,or from about 40% to about 50% by weight of the total weight of thetablet.

Super-Disintegrants.

In further embodiments, the tablet may comprise one or moresuper-disintegrants. Non-limiting examples of suitablesuper-disintegrants include povidone, crospovidine, croscarmellosesodium, sodium starch glycolate, modified starches, modified cellulose,low substituted hydroxypropyl cellulose, calcium silicate, orcombinations thereof. The amount of super-disintegrant included in thetablet may range from about 0.5% to about 50% by weight of the totalweight of the tablet. In embodiments in which a binder is present in thetablet, the amount of binder may range from about 0.5% to about 10%,from about 10% to about 20%, from about 20% to about 30%, from about 30%to about 40%, or from about 40% to about 50% by weight of the totalweight of the tablet.

Lubricants.

In still other embodiments, the tablet may comprise one or morelubricants. Non-limiting examples of suitable lubricants includemagnesium stearate, calcium stearate, zinc stearate, colloidal silicondioxide, hydrogenated vegetable oils, sterotex, polyoxyethylenemonostearate, polyethylene glycol, sodium stearyl fumarate, sodiumoleate, sodium benzoate, sodium lauryl sulfate, magnesium laurylsulfate, light mineral oil, or combinations thereof. The amount oflubricant present in the tablet may range from about 0.1% % to about3.0% by total weight of the tablet. In various embodiments, the amountof lubricant may range from about 0.1% to about 0.5%, from about 0.5% toabout 1.0%, from about 1.0% to about 1.5.5% to about 3.0% by totalweight of the tablet.

Ion-Exchange Resins.

In alternate embodiments, the tablet may comprise one or more ionexchange resin powders. The ion exchange resin powder is selected suchthat it can bind the API if the tablet (or fragments thereof) iscontacted with a suitable solvent, thereby deterring abuse. Most ionexchange resins are based on crosslinked polystyrene or crosslinkedacrylic or methacrylic acid polymers that are modified to containfunctional groups. The ion exchange resin can be anionic or cationic.Cation resins may be weakly acidic (e.g., featuring carboxylic groups)or strongly acidic (e.g., featuring sulfonic acid groups). Anion resinsmay be weakly basic (e.g., featuring primary, secondary, and/or ternaryamino groups) or strongly basic (e.g., featuring quaternary aminogroups). In embodiments in which the tablet contains an ion exchangeresin powder, the amount of ion exchange resin powder may range fromabout 0.5% to about 25% by weight of the total weight of the tablet. Invarious embodiments, the amount of ion exchange resin powder may rangefrom about 0.5% to about 2%, from about 2% to about 5%, from about 5% toabout 10%, from about 10% to about 15%, from about 15% to about 20%, orfrom about 20% to about 25% by weight of the total weight of the tablet.

Aversive Agents.

In certain embodiments, the tablet may further comprise one or moreaversive agents to deter abuse of the dosage form. The aversive agentmay be an irritant, a bittering agent, an emetic, a dye, or acombination thereof. In some embodiments, the aversive agent may be anirritant that causes irritation of mucous membranes located anywhere onor in the body, including membrane of the nose, mouth, eyes, andintestinal tract. Non-limiting examples of suitable irritants, includesurfactants (e.g., sodium lauryl sulfate, alkylbenzene sulfonate, sodiumlaureth sulfate, triethanol ammonium lauryl sulfate, benzalkyoniumchloride), poloxamers, sorbitan monostearate, sorbitan monooleate,glyceryl monostearate, glyceryl monooleate, mustard, allylisothiocyanate, p-hydroxybenzyl isothiocyanate, piperine, niacin,capsaicin, capsaicin analogs (e.g., resiniferatoxin, tinyatoxin,heptanoylisobutylamide, heptanoyl guaiacylamide, dihydrocapsaicin,nordihydrocapsaiscin, homocapsaicin, homodihydrocapsaicin; homovanillyloctylester, nonanoyl vanillylamide), or combinations of any of theforegoing. In other embodiments, the aversive agent may be a bitteringagent that imparts a bitter smell or bitter taste to the tablets ordispersions derived from the tablets. Examples of suitable bitteringagents include without limit denatonium benzoate, denatonium saccharide,denatonium chloride, quinine sulfate, sucrose derivative (e.g., sucroseoctaacetate), chlorosucrose derivatives, benzoic benzylamine amide,trichloroanisole, methyl anthranilate, alkaloids (e.g., sparteine,lupinine), quassinoids (e.g., asquassin, brucine), flavonoids (e.g.,quercetin, naringen), or mixtures thereof. In further embodiments, theaversive agent may be an emetic. In general, the emetic is encapsulatedor physically separated from the other components of the tablet suchthat it has no effect unless the tablet is subjected to physicaltampering or manipulation. Non-limiting examples of suitable emeticsinclude zinc sulfate, apomorphine, xylazine, emetine, ipecacderivatives, or combinations thereof. In yet additional embodiments, theaversive agent may be a dye or coloring agent. Suitable dyes include,without limitation, FD&C Blue No. 2, iron oxides, FD&C Red No. 3, FD&CRed No. 20, FD&C Yellow No. 6, FD&C Blue No. 1, FD&C Green No. 1, FD&CGreen No. 3, FD&C Green No. 5, FD&C Red No. 30, D&C Orange No. 5, D&CRed No. 8, D&C Red No. 33, natural coloring agents such as grape skinextract, beet red powder, beta-carotene, annato, carmine, turmeric,paprika, or combinations thereof. In embodiments in which the tabletcomprises an aversive agent, the amount of aversive agent may range fromabout 0.5% to about 15% by weight of the total weight of the tablet. Incertain embodiments, the amount of aversive agent may range from about0.5% to about 3%, from about 3% to about 6%, from about 6% to about 10%,or from about 10% to about 15% by weight of the total weight of thetablet.

The amount of crush-resistant controlled-release particles present inthe tablet can and will vary depending upon the identity of the API andthe desired dose of API in the tablet. In general, the amount ofparticles present in the tablet may range from about 30% to about 95% byweight of the total weight of the tablet. In various embodiments, theamount of particles present in the tablet may range from about 30% toabout 40%, from about 40% to about 50%, from about 50% to about 60%,from about 60% to about 70%, from about 70% to about 80%, from about 80%to about 90%, or from about 90% to about 95% by weight of the totalweight of the tablet. In various embodiments, the total amount of API inthe tablet may range from about 1 mg to about 400 mg. In embodiments inwhich the API is an opioid analgesic, the amount of opioid in the tabletmay range from about 2 mg to about 160 mg. In various embodiments, theamount of opioid in the tablet may range from about 2 mg to about 10 mg,from about 10 mg to about 40 mg, from about 40 mg to about 80 mg, orfrom about 80 mg to about 160 mg. In certain embodiments, the amount ofopioid in the tablet may be about 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg,17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5 mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg,40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 100 mg, 120 mg, 140 mg, or 160mg.

In one embodiment, the tablet comprises crush-resistantcontrolled-release particles, binder, filler, super-disintegrant, and/orlubricant. In another embodiment, the tablet comprises crush-resistantcontrolled-release particles, binder, filler, super-disintegrant,lubricant, and ion exchange resin powder. In an additional embodiment,the tablet comprises crush-resistant controlled-release particles,binder, filler, super-disintegrant, lubricant, and a nasal irritant asan aversive agent. The nasal irritant may sodium lauryl sulfate. In yetanother embodiment, the tablet comprises crush-resistantcontrolled-release particles, binder, filler, super-disintegrant,lubricant, ion exchange resin powder, and a nasal irritant.

(b) Capsules

In other embodiments, the dosage form is a capsule. Typically, thecapsule is a hard capsule. The shell of the capsule may comprisegelatin, hydrolyzed starch, or a cellulose derivative such ashydroxypropylmethylcellulose (also called hypromellose).

In some embodiments, the capsule consists of a plurality of thecrush-resistant controlled-release particles. In other embodiments, thecapsule comprises a plurality of particles and one or morepharmaceutically acceptable excipients. The pharmaceutically acceptableexcipient(s) may be chosen from gelling polymers, fillers, effervescentsystems, glidants, ion exchange resin powders, or combinations thereof.In some embodiments, the capsule comprising one or more excipients mayfurther comprise at least one aversive agent.

Gelling Polymers.

In some embodiments, the capsule may comprise one or more gellingpolymers. In general, the gelling polymer is a hydrophilic gellingpolymer, which has affinity for water such that, when in contact withwater or a suitable solvent, it readily absorbs water or solvent and/orswells to form a viscous mixture or gel. The resultant viscous mixture,therefore, is difficult to draw into a syringe, making it difficult orimpossible to inject the mixture and/or extract the API from themixture. The gelling polymer, therefore, is included in the capsuledosage form to deter abuse of the formulation. Non-limiting examples ofsuitable hydrophilic gelling polymers include cellulose ethers (e.g.,hydroxypropylcellulose, hydroxypropylmethylcellulose, sodiumcarboxymethyl cellulose, methylcellulose, hydroxyethylcellulose, and thelike), polyalkylene oxides (e.g., polyethylene oxide, polypropyleneoxide, derivatives thereof, copolymers thereof, or combinationsthereof), natural gums (e.g., glucomannan, guar gum, gum arabic, gumtragacanth, tara gum, alginate, alginic acid, fucoidan, laminarin, agar,carrageenans, xanthan gum, gellan gum, dextran, welan gum, diutan gum,pullulan, derivatives thereof, or combinations thereof), polyacrylicacids or crosslinked polyacrylic acids (e.g., carbomers), polyvinylalcohol, polyvinylpyrrolidone, polyamines, or combinations of any of theforegoing. The average molecular weight of the gelling polymer may rangefrom about 30,000 to about 15,000,000. In embodiments in which a gellingpolymer is present in the capsule, the amount of gelling polymer mayrange from about 0.1% to about 50% by weight of the contents of thecapsule. In some embodiments, amount of gelling polymer may range fromabout 0.1% to 10%, from about 10% to about 20%, from about 20% to about30%, from about 30% to about 40%, or from about 40% to about 50% byweight of the contents of the capsule.

Fillers.

In other embodiments, the capsule may comprise one or more fillers (alsocalled diluents). Suitable fillers include without limit cellulose,microcrystalline cellulose, cellulose derivatives (e.g., calciumcarboxymethyl cellulose, ethyl cellulose), starch, modified starches,pregelatinized starch, glucose/dextrose, fructose, sucrose, lactose,mannitol, sorbitol, xylitol, calcium carbonate, calcium sulfate, calciumphosphate, calcium silicate, magnesium carbonate, magnesium oxide, orcombinations thereof. In embodiments in which filler is present in thecapsule, the amount of filler may range from about 0.1% to about toabout 50% by weight of the contents of the capsule. In variousembodiments, the amount of filler may range from about 0.1% to about10%, from about 10% to about 20%, from about 20% to about 30%, fromabout 30% to about 40%, or from about 40% to about 50% by weight of thecontents of the capsule.

Effervescent Systems.

In still other embodiments, the capsule may comprise an effervescentsystem. As used herein, an “effervescent system” refers to a systemgenerally comprising an acid component and a base component, wherein thesystem liberates carbon dioxide upon contact with an aqueous solution.The acid component of the effervescent system may be an organic acid, aninorganic acid, or combinations thereof. Non-limiting examples ofsuitable acids include adipic acid, ascorbic acid, benzoic acid, citricacid, disodium pyrophosphate, fumaric acid, glutaric acid, hexamic acid,lactic acid, lauric acid, malic acid, maleic acid, malonic acid, oxalicacid, phthalic acid, potassium bitartrate, sodium acid pyrophosphate,sodium dihydrogen phosphate, sorbic acid, succinic acid, tartaric acid,or combinations thereof. The base component of the effervescent systemmay be a base chosen from a carbonate, a bicarbonate, or combinationsthereof. Examples of suitable bases include, without limit, ammoniumbicarbonate, potassium bicarbonate, sodium bicarbonate, argininecarbonate, ammonium carbonate, calcium carbonate, lysine carbonate,potassium magnesium carbonate, sodium carbonate, sodium glycinecarbonate, sodium sesquicarbonate, zinc carbonate, or combinationsthereof. The mole ratio of the acid component to the base component inthe effervescent system may be about 1:3, about 1:2, about 1:1, about2:1, about 3:1, or any ratio in-between. In embodiments in which aneffervescent system is present in the capsule, the amount ofeffervescent system may range from about 1% to about to about 50% byweight of the contents of the capsule. In various embodiments, theamount of effervescent system may range from about 1% to about 10%, fromabout 10% to about 20%, from about 20% to about 30%, from about 30% toabout 40%, or from about 40% to about 50% by weight of the contents ofthe capsule.

Glidants.

In alternate embodiments, the capsule may comprise one or more glidants.Glidants improve the flowability of powders or granular mixtures.Non-limiting examples of suitable glidants include colloidal silica,colloidal silicon dioxide, cellulose, calcium phosphate (di or tribasic), fumed silica, hydrated magnesium carbonate, sodiumsilioaluminate, starch, talc, micronized talc, or combinations thereof.In embodiments in which a glidant is present in the capsule, the amountof glidant may range from about 0.1% to about to about 10% by weight ofthe contents of the capsule. In certain embodiments, the amount of mayrange from about 0.1% to about 0.5%, from about 0.5% to about 1.0%, fromabout 1.0% to about 1.5.5% to about 3.0% by total weight of the contentsof the capsule.

Ion-Exchange Resins.

In yet other embodiments, the capsule may comprise one or more ionexchange resin powders. The ion exchange resin powder is selected suchthat it can bind the API if the capsule (or contents thereof) iscontacted with a suitable solvent, thereby deterring abuse. The ionexchange resin powder can be anionic or cationic. Anion resins may beweakly acidic (e.g., featuring carboxylic groups) or strongly acidic(e.g., featuring sulfonic acid groups). Cation resins may be weaklybasic (e.g., featuring primary, secondary, and/or ternary amino groups)or strongly basic (e.g., featuring quaternary amino groups). Inembodiments in which the capsule contains an ion exchange resin powder,the amount of ion exchange resin powder may range from about 0.5% toabout 25% by weight of the contents of the capsule. In variousembodiments, the amount of ion exchange resin powder may range fromabout 0.5% to about 2%, from about 2% to about 5%, from about 5% toabout 10%, from about 10% to about 15%, from about 15% to about 20%, orfrom about 20% to about 25% by weight of the contents of the capsule.

Aversive Agents.

In certain embodiments, the capsule may further comprise an aversiveagent to deter abuse of the dosage form. The aversive agent may be anirritant, a bittering agent, an emetic, a dye, or a combination thereof.In some embodiments, the aversive agent may be an irritant that causesirritation of mucous membranes located anywhere on or in the body,including membrane of the nose, mouth, eyes, and intestinal tract.Non-limiting examples of suitable irritants, include surfactants (e.g.,sodium lauryl sulfate, alkylbenzene sulfonate, sodium laureth sulfate,triethanol ammonium lauryl sulfate, benzalkyonium chloride), poloxamers,sorbitan monostearate, sorbitan monooleate, glyceryl monostearate,glyceryl monooleate, mustard, allyl isothiocyanate, p-hydroxybenzylisothiocyanate, piperine, niacin, capsaicin, capsaicin analogs (e.g.,resiniferatoxin, tinyatoxin, heptanoylisobutylamide, heptanoylguaiacylamide, dihydrocapsaicin, nordihydrocapsaiscin, homocapsaicin,homodihydrocapsaicin; homovanillyl octylester, nonanoyl vanillylamide),or combinations of any of the foregoing. In other embodiments, theaversive agent may be a bittering agent that imparts a bitter smell orbitter taste to the tablets or dispersions derived from the tablets.Examples of suitable bittering agents include without limit denatoniumbenzoate, denatonium saccharide, denatonium chloride, quinine sulfate,sucrose derivative (e.g., sucrose octaacetate), chlorosucrosederivatives, benzoic benzylamine amide, trichloroanisole, methylanthranilate, alkaloids (e.g., sparteine, lupinine), quassinoids (e.g.,asquassin, brucine), flavonoids (e.g., quercetin, naringen), or mixturesthereof. In further embodiments, the aversive agent may be an emetic. Ingeneral, the emetic is encapsulated or physically separated from theother components of the capsule such that it has no effect unless thecapsule is tampering with or manipulated. Non-limiting examples ofemetics include zinc sulfate, apomorphine, xylazine, emetine, ipecacderivatives, or combinations thereof. In yet additional embodiments, theaversive agent may be a dye or coloring agents. Suitable dyes include,without limitation, FD&C Blue No. 2, iron oxides, FD&C Red No. 3, FD&CRed No. 20, FD&C Yellow No. 6, FD&C Blue No. 1, FD&C Green No. 1, FD&CGreen No. 3, FD&C Green No. 5, FD&C Red No. 30, D&C Orange No. 5, D&CRed No. 8, D&C Red No. 33, natural coloring agents such as grape skinextract, beet red powder, beta-carotene, annato, carmine, turmeric,paprika, or combinations thereof. In embodiments in which the capsulecomprises an aversive agent, the amount of aversive agent may range fromabout 0.5% to about 15% by weight of the total weight of the contents ofthe capsule. In certain embodiments, the amount of aversive agent mayrange from about 0.5% to about 3%, from about 3% to about 6%, from about6% to about 10%, or from about 10% to about 15% by weight of the totalweight of the contents of the capsule.

The amount of crush-resistant controlled-release particles present inthe capsule can and will vary depending upon the identity of the API andthe desired dose of API in the capsule. In general, the amount ofcrush-resistant controlled-release particles present in the capsule mayrange from about 5% to about 100% by weight of the contents of thecapsule. In various embodiments, the amount of particles present in thecapsule may range from about 5% to about 15%, from about 15% to about3-%, from about 30% to about 40%, from about 40% to about 50%, fromabout 50% to about 60%, from about 60% to about 70%, from about 70% toabout 80%, from about 80% to about 90%, or from about 90% to about 100%by weight of the contents of the capsule. In various embodiments, thetotal amount of API in the capsule may range from about 1 mg to about400 mg. In embodiments in which the API is an opioid analgesic, theamount of opioid in the capsule may range from about 2 mg to about 160mg. In various embodiments, the amount of opioid in the capsule mayrange from about 2 mg to about 10 mg, from about 10 mg to about 40 mg,from about 40 mg to about 80 mg, or from about 80 mg to about 160 mg. Incertain embodiments, the amount of opioid in the tablet may be about 5mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, 20 mg, 22.5 mg, 25 mg, 27.5mg, 30 mg, 32.5 mg, 35 mg, 37.5 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg,80 mg, 100 mg, 120 mg, 140 mg, or 160 mg.

In one embodiment, the capsule consists of crush-resistantcontrolled-release particles. In another embodiment, the capsulecomprises crush-resistant controlled-release particles, gelling polymer,filler, effervescent system, and/or glidant. In still anotherembodiment, the capsule comprises crush-resistant controlled-releaseparticles, gelling polymer, filler, effervescent system, glidant, ionexchange resin powder, and/or nasal irritant as an aversive agent. Thenasal irritant may be sodium lauryl sulfate.

(c) In Vitro Release Profile of the Dosage Forms

The rate of dissolution of the dosage forms described above can and willvary depending on the type and/or amount of pharmaceutically acceptableexcipients that may be present. In some embodiments, the dosage form maydisintegrate or dissolve very rapidly. The rate of release of the APIfrom the dosage form, however, parallels the rate of API release fromthe crush-resistant controlled-release particles. As detailed in section(I)(i) above, in vitro release of the API from the particles occurs overan extended period of time. Thus, in vitro release of the API from thedosage form also occurs over an extended period of time. For example,the total amount of API in the dosage form may be released over about 8hours, over about 12 hours, over about 18 hours, or over about 24 hours.

(d) Abuse Deterrent Properties of the Dosage Forms

In embodiments in which the dosage form is tablet, the tablet may becrushed, ground, milled, or pulverized, but the crush-resistantparticles will not be affected by the crushing, grinding, milling, orpulverizing (see section (I)(h) above). Likewise, in embodiments inwhich the dosage form is a capsule and the contents are removed from thecapsule, the crush-resistant particles remain resistant to crushing,grinding, milling, or pulverizing. The crush-resistant particles,therefore, deter intranasal abuse by grinding or milling and/or deteroral abuse by chewing (pulverizing).

The dosage forms may also contain other agents that help deter abuse. Insome embodiments, the dosage form may contain a gelling polymer or abinder/filler that forms a viscous mixture or gel when said dosage formis contacted with a small volume (<10 ml) of suitable solvent. Theresultant viscous mixture is difficult to draw into a syringe, therebydeterring abuse by intravenous injection. Additionally, the API isdifficult to extract from said viscous mixture, deterring intravenousinjection or oral abuse after extraction of the API.

In other embodiments, the dosage form may contain an ion exchange resinpowder that binds the API when said dosage form is contacted with asuitable solvent. The resultant homogenous solution is devoid of API,thereby deterring abuse by intravenous injection.

In still other embodiments, the dosage form may contain an aversiveagent (e.g., irritant, bittering agent, emetic, and/or dye). Theaversive agent makes oral, parental, or nasal administration of atampered dosage form aversive or unpleasant.

(III) Processes for Preparing Particles and Dosage Forms

Also provided herein are processes for preparing the crush-resistantcontrolled release particles and dosage forms comprising thecrush-resistant controlled release particles.

(a) Preparing Particles

The crush-resistant controlled-release particles described above insection (I) are prepared by a hot melt extrusion process. Hot meltextrusion (HME) is the process of applying heat and pressure to melt apolymer and force it though an orifice in a continuous process. Examplesof pharmaceutical-class extruders, principles of operation, and processtechnology are detailed in Crowley et al. (Drug Development andIndustrial Pharmacy, 2007, 33(9):909-926). The particles disclosedherein are prepared by a process comprising blending the plastic/elasticpolymer(s), the API or salt thereof, and other components of theparticles to form a blend, hot melt extruding the blend to form anextrudate, and pelletizing/milling the extrudate to form the particles.

The first step of the process comprises blending the components of theparticles. Examples of suitable plastic/elastic polymers, plasticizers,lubricants, wetting agents, and APIs are provided above in sections(I)(a)-(e). The components may be combined in any order or may bepremixed in various combinations before being combined together andblended. For example, the plastic/elastic polymers may be blended withliquid plasticizers and/or wetting agents prior to being blended withthe other components. The components can be blended by mixing, rollermixing, drum mixing, shear mixing, dry blending, chopping, milling,granulating, dry granulating (e.g., slugging or roller compacting), wetgranulating (e.g., fluid bed granulating, high shear granulating), andother mixing techniques known in the art, thereby forming a blend.

The next step of the process comprises hot melt extruding the blend toform an extrudate. In general, the hot melt extruding is performed usingconventional screw extruders, e.g., single screw extruder ortwin-screw-extruder. Temperatures may range from about 60° C. to about250° C. with a pressure range of 0 to 150 bar. In some embodiments, theextrudate may be cooled and/or dried by conventional means.

The final step of the process comprises pelletizing/milling theextrudate to form particles. The extrudate can be cut into pieces bymeans of revolving or rotating knives, water jet cutters, wires, bladesor with the assistance of laser cutter. Rod-shaped extrudate can bechopped into pellets or granules using a pelletizing machine.Alternatively, the extrudate can be press-molded into the desired pelletshape. Extrudate pieces or pellets can be milled in a milling machine(e.g., vertical mill, horizontal mill) to form particles having anaverage particle size distribution from about 50 micrometers to about1500 micrometers.

(b) Preparing Tablets

The tablets comprising the hot melt extruded particles can be preparedusing conventional methods known to those in the field of pharmaceuticalformulation and described in the pertinent texts, e.g., in Gennaro, A.R., editor. “Remington: The Science & Practice of Pharmacy”, 21st ed.,Williams & Williams, and in the “Physician's Desk Reference”, 2006,Thomson Healthcare. In particular, tablets comprising the hot meltextruded particles described above are prepared by blending thecomponents of the tablet to form a mixture, forming the mixture intotablets, and optionally coating the tablets with a film coating.

The first step comprises blending the hot melt extruded particlesdescribed above with additional tablet components (i.e., binder, filler,super-disintegrant, lubricant, ion exchange resin powder, and/oraversive agent) described above in section (II)(a). The components canbe combined in any order or may be premixed in various combinationsbefore being combined together. The components can be blended by mixing,roller mixing, drum mixing, shear mixing, dry blending, chopping,milling, granulating, dry granulating (e.g., slugging or rollercompacting), wet granulating (e.g., fluid bed granulating, high sheargranulating), and other mixing techniques known in the art.

The process further comprises forming the mixture into a tablet. Tabletforming techniques are well known in the art. The tablet may be acompression tablet, a molded tablet, a compacted tablet, or a pressedtablet. The shape and size of the tablet may vary. In a preferredembodiment, the tablet may be formed by direct compression. The amountof compression applied to the mixture can and will vary depending uponthe desired dissolution profile of the tablet.

The tablet may be coated with a film coating. The film coating does notaffect the extended release or abuse deterrent properties of the tabletdosage forms. The film coating may be spray coated onto the dosage form.The spray coating system by be a bottom spray coating system, a topspray coating system, a tangential spray coating system, a pan coatingsystem, or another suitable coating system.

Film coatings are well known in the art, e.g., some are commerciallyavailable, e.g., under the trade name OPADRY®. Typically, a film coatingcomprises at least one water-soluble polymer and at least oneplasticizer. Non-limiting examples of suitable polymers includehydroxypropylmethyl cellulose, hydroxypropyl cellulose,hydroxypropylethyl cellulose, ethyl cellulose, methyl cellulose,cellulose acetate phthalate, microcrystalline cellulose and carrageenan,acrylic polymers, polyvinyl alcohol, anionic and cationic polymers ofmethacrylic acid, copolymers of methacrylates, copolymers of acrylatesand methacrylates, copolymers of ethacrylate and methyl methacrylate,polyvinylacetate phthalate, and shellac. Examples of suitableplasticizers include, without limit, triethyl citrate (TEC),acetyltriethyl citrate (ATEC), acetyl tri-n-butyl citrate (ATBC),dibutyl sebacate, diethyl phthalate, and triacetin. The film coating mayoptionally comprise additional agents such as coloring agents, fillers,flavoring agents, taste-masking agents, surfactants, anti-tackingagents, and/or anti-foaming agents. Suitable examples of these agentsare well known in the art.

(c) Preparing Capsules

The capsules containing the hot melt extruded particles are preparedassembling and encapsulating the components into the capsules. Means forpreparing and filling hard-shelled capsules are well known in the art.

In some embodiments, the process comprises encapsulating the hot meltextruded particles into capsules. In other embodiments, the processcomprises blending the hot melt extruded particles with other capsulecomponents (i.e., gelling polymer, filler, effervescent system, glidant,ion exchange resin powder, and/or aversive agent) to form a mixture andthen encapsulating the mixture into capsules.

Definitions

Compounds useful in the compositions and methods include those describedherein in any of their pharmaceutically acceptable forms, includingisomers such as diastereomers and enantiomers, salts, solvates, andpolymorphs, as well as racemic mixtures and pure isomers of thecompounds described herein, where applicable.

When introducing elements of the present invention or the preferredembodiments(s) thereof, the articles “a”, “an”, “the” and “said” areintended to mean that there are one or more of the elements. The terms“comprising”, “including” and “having” are intended to be inclusive andmean that there may be additional elements other than the listedelements.

The term “about,” particularly in reference to a given quantity, ismeant to encompass deviations of plus or minus five percent.

As used herein, “abuse deterrent” refers to any property or feature of apharmaceutical composition that lessens the potential for abuse of theactive ingredient(s) in the composition.

EXAMPLES

The following examples are included to demonstrate preferred embodimentsof the present disclosure. It should be appreciated by those of skill inthe art that the techniques disclosed in the examples representtechniques discovered by the inventors to function well in the practiceof the invention. Those of skill in the art should, however, in light ofthe present disclosure, appreciate that many changes can be made in thespecific embodiments that are disclosed and still obtain a like orsimilar result without departing from the spirit and scope of theinvention, therefore all matter set forth is to be interpreted asillustrative and not in a limiting sense.

Example 1: Crush-Resistant Controlled-Release Particle System (CRCRPS)

A crush-resistant controlled-release particulate system (CRCRPS) wasprepared by a hot melt extrusion and milling process. The composition ofthe CRCRPS is provided in Table 1. KOLLIDON® SR contains 80% polyvinylacetate (MW 450,000), 19% povidone (MW 50,000), 0.8% sodium laurylsulfate, and 0.2% silicon dioxide. The ingredients were dry blended andhot melt extruded on a Pharma 11 twin screw extruder with temperaturesas high as 130° C. with a pressure of 25 bar. The extrudate was milledinto particles of the desired particle size distribution. The D50 of theparticles was about 800 μm.

TABLE 1 Compositions of CRCRPS Material % mg/dosage Oxycodone HCL 14 40KOLLIDON ® SR 60-65 171.4-185.7 Diethyl phthalate    9-14.25 25.7-40.7Polyethylene Glycol 300 0.75-6    2.1-17.1 Polyethylene Oxide N10 0-5  0-14.3 (MW 100,000) Magnesium stearate  1    2.86

Example 2: In Vitro Dissolution Profile of CRCRPS Before and afterGrinding

An aliquot of CRCRPS (prepared as described in Example 1) was ground for2 minutes in a coffee grinder. Particle size before and after grindingwas determined using a Malvern particle size analyzer. The D10 and D50values before and after grinding are presented in Table 2. The particlesize was reduced only 20-25% after two minutes of grinding.

TABLE 2 Crush Resistance of CRCRPS D10 μm D50 μm Before grinding 590 818After grinding 442 654

The in vitro dissolution profile of CRCRPS before and after grinding wasmeasured in 900 mL of simulated gastric fluid (SGF) using an USP type 2paddle apparatus with a paddle speed of 50 rpm and a constanttemperature of 37° C. Samples were removed at various time points from0.2 hr to 8 hr and analyzed by HPLC for oxycodone hydrochloride. FIG. 1presents the dissolution profiles of CRCRPS before and after grinding ina coffee grinder. The dissolution profile of the “ground” CRCRPSmirrored that of the “intact” particles. Both samples exhibited extendedrelease, i.e., released less than 70% of oxycodone HCL within 8 hr.

Example 3: Effects of Grinding on Particle Size Distribution

Aliquots of CRCRPS (as prepared in Example 1) were ground for 60seconds, 180 seconds, or 255 seconds and the percentage of particles ofvarious sizes was estimated by screening. A shown in Table 3, thepercentage of large particles (i.e., retained by 25 mesh screen orbeing >0.71 mm) increased after more than 3 minutes of grinding.

TABLE 3 Effect of Grinding Time on Particle Size Distribution MillingTime Weight >0.71 mm >0.25 mm >20 μm (s) (g) % % % 1 60 3.000 57.8 39.92.3 2 180 2.9213 44.8 52.3 2.7 3 255 2.917 77.1 22.2 0.8

Increasing amounts of CRCRPS (i.e., 1 x dosage to 20 x dosage) wereground for 3 minutes. The results are shown in Table 4.

TABLE 4 Effect of Mass on Particle Size Distribution Milling TimeWeight >0.71 mm >0.25 mm >20 μm (s) (g) % % % 1 180 0.294 80.8 16.4 1.32 180 1.461 72.7 25.7 1.2 3 180 2.923 44.8 52.3 2.7 4 180 5.843 64.733.2 2.0

Example 4: Dosage Forms Comprising CRCRPS

Table 5 lists the components of exemplary dosage forms.

TABLE 5 Compositions of Dosage Forms Material mg/dosage CRCRPS 285.7 Ionexchange resin powder 40 Nasal irritant (sodium lauryl sulfate) 30 Superdisintegrant 100 Magnesium stearate 1.15

What is claimed is:
 1. An extended release, abuse deterrent dosage formcomprising a plurality of particles and at least one pharmaceuticallyacceptable excipient, wherein the plurality of particles consists of atleast one active pharmaceutical ingredient (API) or a pharmaceuticallyacceptable salt thereof, at least one polyvinyl ester, at least onepoly-N-vinylamide, at least one plasticizer, at least one optionallubricant, at least one optional polyalkylene oxide, and at least oneoptional wetting agent.
 2. The extended release, abuse deterrent dosageform of claim 1, wherein the at least one API is oxycodone, oxymorphone,hydrocodone, hydromorphone, codeine, or morphine.
 3. The extendedrelease, abuse deterrent dosage form of claim 1, wherein the at leastone polyvinyl ester is polyvinyl acetate.
 4. The extended release, abusedeterrent dosage form of claim 1, wherein the at least onepoly-N-vinylamide is polyvinylpyrrolidone.
 5. The extended release,abuse deterrent dosage form of claim 1, wherein the at least oneplasticizer is polyethylene glycol, propylene glycol, glycerin,polyethylene glycol monomethyl ether, sorbitol sorbitan solution,triethyl cellulose, dicarboxylic acid ester, acetyl tributyl citrate,acetyl triethyl citrate, castor oil, vegetable oil, diacetylatedmonoglyceride, dibutyl sebacate, diethyl phthalate, triacetin,tributyrin, tributyl citrate, triethyl citrate, polaxamer, orcombination thereof.
 6. The extended release, abuse deterrent dosageform of claim 1, wherein the at least one optional lubricant ismagnesium stearate, calcium stearate, zinc stearate, colloidal silicondioxide, hydrogenated vegetable oil, sterotex, polyoxyethylenemonostearate, polyethylene glycol, sodium stearyl fumarate, sodiumbenzoate, sodium lauryl sulfate, magnesium lauryl sulfate, light mineraloil, or combination thereof.
 7. The extended release, abuse deterrentdosage form of claim 1, wherein the at least one optional polyalkyeneoxide is polyethylene oxide having an average molecular weightdistribution from about 100,000 to about 7,000,000.
 8. The extendedrelease, abuse deterrent dosage form of claim 1, wherein the at leastone optional wetting agent is polyoxyethylene glycol alkyl ether,polyoxyethylene glycol sorbitan alkyl ester, polyethylene glycol ester,sorbitan fatty acid ester, glyceryl fatty acid esters, polyethyleneglycol, block co-polymer of polyethylene glycol and polypropyleneglycol, polaxamer, polyoxyethylene fatty acid amide, polysorbate,ethoxylated aliphatic alcohol, alkylphenol, alkyl sulfate, alkylsulfonate, alkyl benzene sulfonate, alpha sulfonyl fatty acid, alkylphosphate, dioctyl sulfosuccinate, isethionate, alkyl ether sulfate,methyl sarcosine, alkyltrimethylammonium bromide, cetyltrimethylammoniumbromide, benzalkonium chloride; benzethonium chloride,(3-((3-cholamidopropyl) dimethylammonio)-1-propanesulfonate (CHAPS),lecithin, cocoaminopropyl betaine, or combination thereof.
 9. Theextended release, abuse deterrent dosage form of claim 1, wherein theplurality of particles has an average particle size distribution fromabout 100 micrometers to about 1000 micrometers.
 10. The extendedrelease, abuse deterrent dosage form of claim 1, wherein the pluralityof particles is resistant to crushing, grinding, milling, or pulverizingto form a powder comprising particles having an average diameter of lessthan about 10 micrometers.
 11. The extended release, abuse deterrentdosage form of claim 1, wherein the plurality of particles releases theAPI over an extended period of time when the dosage form is crushed,broken, ground, milled, or pulverized.
 12. The extended release, abusedeterrent dosage form of claim 1, wherein the dosage form is formulatedfor oral delivery.
 13. The extended release, abuse deterrent dosage formof claim 12, wherein the dosage form is a tablet.
 14. The extendedrelease, abuse deterrent dosage form of claim 13, wherein the at leastone pharmaceutically acceptable excipient is a binder, a filler, asuper-disintegrant, a lubricant, an ion exchange resin powder, or acombination thereof.
 15. The extended release, abuse deterrent dosageform of claim 13, wherein the tablet further comprises an aversive agentchosen from an irritant, a bittering agent, an emetic, a dye, or acombination thereof.
 16. The extended release, abuse deterrent dosageform of claim 12, wherein the dosage form is a capsule.
 17. The extendedrelease, abuse deterrent dosage form of claim 16, wherein the at leastone pharmaceutically acceptable excipient is a gelling polymer, afiller, an effervescent system, a glidant, an ion exchange resin powder,or a combination thereof.
 18. The extended release, abuse deterrentdosage form of claim 16, wherein the capsule further comprises anaversive agent chosen from an irritant, a bittering agent, an emetic, adye, or a combination thereof.
 19. The extended release, abuse deterrentdosage form of claim 1, wherein the at least one polyvinyl ester ispolyvinyl acetate; the at least one poly-N-vinylamide ispolyvinylpyrrolidone; the at least one plasticizer is diethyl phthalateor a combination of diethyl phthalate and polyethylene glycol; the atleast one optional polyalkylene oxide is polyethylene oxide; the atleast one optional lubricant is present and is magnesium stearate,silicon dioxide, or a combination thereof; and the at least one optionalwetting agent is present and is sodium lauryl sulfate.
 20. The extendedrelease, abuse deterrent dosage form of claim 19, wherein the at leastone API is oxycodone, oxymorphone, hydrocodone, hydromorphone, codeine,or morphine.